Fused bicyclic pyrrolidines

Azaallyl anion cycloadditions. Imines bearing one or more aryl groups are converted by LDA into 2-azaallyl anions. These anions undergo cycloaddition not only with activated alkenes,2 but can also undergo intramolecular cycloaddition with a double bond to form as-fused bicyclic pyrrolidines.3... 

Unactivated dipolarophiles readily participate in intramolecular azomethine ylide cycloadditions with a more reactive azomethine ylide. Thus, flash vacuum pyrolysis of aziridine (113) afforded a 67% yield of the 5,5-fused bicyclic pyrrolidine (Scheme 34).59 A singly stabilized azomethine ylide was the apparent intermediate. Similarly, cyclization of the azomethine ylides derived from (114a-c) gave the corresponding cw-fused 6,6-bicyclic pyrrolidines in 69%, 26% and 16% yield, respectively the original double bond stereochemistry was retained in the latter two cases. 

Confalone and Earl have reported a series of intramolecular azomethine ylide cyclizations employing a-dithiolanyl aldehydes (Scheme 35).60 Thus, reaction of the aldehydes (115a-b) with ethyl sarcosinate at 140 C provided the 5,6-fused bicyclic pyrrolidines (116a-b), presumably via cyclization of the singly stabilized azomethine ylides. The dithiolanyl group could be removed by standard reactions this route then provides bicyclic pyrrolidines which cannot be prepared directly from enolizable aldehydes. 

The efficient catalytic cyclization (aminocarbonylation) of A-(3-hydroxy-4-pentenyl)amides and carbamates in acetic acid gave m-fused bicyclic pyrrolidine lactone compounds54,56 (Table 2), in agreement with the observed ra-directing capability of the hydroxy group in analogous electrophile mediated additions (Section 7.2.6). In tetrahydrofuran the reaction rate is unacceptably low. In methanol a competitive allylic substitution leads to 1,2,5,6-tetrahydropyridines. Furthermore, lower yields were obtained in the cyclization of the corresponding ureas. 

Intramolecular cycloadditions are among the most efficient methods for the synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine skeleton encompasses two key retro-cycloaddition key elements. (1) a bridging pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a [2.2.2] bicyclo-octane accessible via a [4+2] Diels-Alder carbocyclic cycloaddition (Chart 1.4). While intramolecular [4+2] Diels—Alder cycloadditions to form [2.2.2] bicycle-octane systems have extensive precedence [3+2], azomethine dipolar cycloadditions to form highly fused aza systems are rare [31-33]. The staging of these two operations in sequence is critical to a unified synthetic plan. As the proposed [3+2] dipolar cycloaddition is expected to be the more challenging of the two transformations, it should be conducted in an early phase in the forward synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C-C bond disconnections for this transformation. 

The fused 4/5/5 system has been obtained by ring closure forming the lactam ring on a bicyclic pyrrolidine (Equation 62) <1998JOC8170>. Michael addition to an unsaturated lactone was used to form the middle ring of compound 409 (Equation 63) <1999T3427>. 

Fluorous aminoesters have also been used in DOS of three unique triaza tricyclic and tetracyclic ring systems (Scheme 22) [44], Bicyclic pyrrolidines 12 generated from one-pot, three-component 1,3-dipolar cycloaddition of azomethine ylides were further converted to hydantoin-, piperazinedione-, and benzodiazepine-fused compounds 31-33, respectively. Each of these three heterocyclic scaffolds has four stereocenters on the central pyrrolidine ring and up to four points of diversity (R1 to R4). The structure of compound... 

When the related aziridine 195 was used containing one less carbon in the tether, an unusual cyclization occurred which corresponds to a formal [3+2] aziridine allylsilane cycloaddition to give the bicyclic pyrrolidine 196. This substrate was used for the preparation of other fused ring systems (Scheme 53) <1999T8025>. 

The use of cyclic enamines" > " " b.436,441,443,446.447, 456.457,470-480 (-g g UQ o ) or dieneamines (e.g., 141 ) yields fused bicyclic systems, although the latter may also yield bis-thietane sulfones. Enamines derived from morpholine, piperidine, pyrrolidine, and dimethylamine are most commonly used, but derivatives of diethylamine, di- -propyl-amine, piperazine, 4-benzylpiperidine, methylpyrrolidines, hexahydroazepin, N-methylaniline, and indoline have also been treated with sulfenes to give thietane sulfones. Asymmetric induction has been observed with the optically active enamine, 142. ... 

Two transformations should be discussed in more detail (1) presence of the amino group in 275 was utilized for the synthesis of the fused isoquinolinium salt 276 bearing the bicyclic heterocycle as an A-substituent <2003JHC1041> (2) selective nucleophilic substitution of 277 with pyrrolidine was reported <2001ZOR604> to yield only substitution on the phenyl substituent without formation of an amide from the ester group 278. 

The diastereoselectivity is reversed in the alkylation of the enolate derived from the structurally very similar bicyclic lactam, tetrahydro-3-phenyl-l//.577-pyrrolof 1,2-c]oxazol-5-one (3). Thus, the major diastereomer 4 produced has the tram relationship between the newly introduced substituent in the pyrrolidine ring and the fused oxazolidine ring residue11,12. Only active electrophiles such as iodomethane, 3-halopropenes or (halomethyl)benzenes react11,12. Base-catalyzed equilibration of the product obtained by reaction with 3-bromocyclohexene gives a 50 50 mixture of the cis- and rra s-diastereomers11. 

Conjugate addition to (35 ,7a/ )-3,7a-dihydro-3-phenyl-l//,5f/-pyrrolof1,2-r ]oxazol-5-onc (8) yields the saturated -substituted bicyclic lactams 9 with complete diastereoselectivity13. Treatment of the latter with 2.2 equivalents of lithium diisopropylamide in tetrahydrofuran at — 78 °C, followed by alkylation with a haloalkane, furnishes the a,/i-dialkylatcd products 10 with excellent selectivity (d.r. >98.5 1.5, determined by H and 13CNMR)13. In this case the major diastereomer has the cw-relationship between the newly introduced substituent (R2) in the pyrrolidine ring and the fused oxazolidinc ring rcsiduc13. 

Indolizines, indolizidines, indoles, and other bicyclic or polycyclic compounds containing a fused pyrrole or pyrrolidine moiety often possess potent and useful biological activities. There have been several approaches to the preparation of fluorinated analogues of these heterocycles, mainly based on 1,3-dipolar addition reactions using fluorinated synthons either as the dipole or as the dipolarophile. Several examples of this strategy are given below. 

Synthesis of novel phosphoproline derivatives (562) in which the six-membered carboeyele was fused to the [c] instead of the [d faee of pyrrolidine, thus giving rise to an octahydroisoindole instead of an oeta-hydroindole bicyclic system, has been deseribed by Cativiela et n/. ... 

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